Blepharitis is a chronic disorder producing inflammation of the anterior and posterior lid margin, with involvement of skin and its related structures (hairs and sebaceous glands), the mucocutaneous junction, and the meibomian glands. It can also affect the conjunctiva, tear film, and the corneal surface in advanced stages and may be associated with dry eye. Blepharitis is commonly classified into anterior or posterior blepharitis, with anterior affecting the lash bearing region of the lids, and posterior primarily affecting the meibomian gland orifices (American American Academy of Opthalmology, Blepharitis. 2003; Thygeson, Arch Opthalmol., 1946, 36:938-942; Foulks, Ocul Surf 2003; 1(3):107-120). Blepharitis is one of the most common ocular disorders seen by ophthalmologists and has no cure to date or FDA-approved treatments for this condition.
Blepharitis in its mild form is usually undiagnosed and rarely managed. In one study, the prevalence of blepharitis was estimated at 10% in the general population (Claoue, Eye, 1997, 11(6):865-868) but is probably higher in the elderly. Between 30% and 50% of patients with blepharitis also have keratoconjunctivitis sicca (Wu, In: Lee D A, Higginbotham E J, eds. Clinical Guide to Comprehensive Opthalmology, 1st ed. Thieme Medical Pub, 1999:189). Blepharitis, with or without a dry eye component, is associated with a broad spectrum of ocular symptoms ranging from mild transient irritation to persistent irritation, burning, itching, redness, pain, ocular fatigue and vision disturbances.
Blepharitic changes limited primarily to the posterior lid margin arise predominantly from pathological processes centered around the meibomian glands. The meibomian glands are holocrine glands that supply the lipids, which form the external oily layer of the precorneal tear film. It is the alteration in this excretory process and the composition of tear film lipids that cause the clinical manifestations seen with this disease.
Clinical and laboratory investigations in recent years have identified several forms of meibomian gland disease/dysfunction (MGD). McCulley et al. (Opthalmology, 1982, 89: 1173-1180) have described three forms of meibomitis characterized by biomicroscopic changes in the meibomian glands and ducts. “Secondary meibomitis” represents a localized inflammatory response in which the meibomian glands are secondarily inflamed in a spotty fashion from an anterior lid margin blepharitis. Both “meibomian seborrhea” and “primary meibomitis” produce generalized gland dysfunction, but differ with regard to the underlying glandular abnormality. Meibomian seborrhea is characterized by excessive meibomian secretion in the absence of inflammation (hypersecretory form). Primary meibomitis, by contrast, is distinguished by stagnant and inspissated meibomian secretions (obstructive form).
Acne rosacea, seborrheic dermatitis, psoriasis, atopy and hypersensitivity to bacterial products may all contribute to the etiology of blepharitis (Cher, Mod Med Austr., 1997, 52-62). It is generally assumed that infection plays a role in anterior blepharitis (Thygeson, 1946; Dougherty, 1984; Smith, CLAO J., 1995, 21(3):200-207), and cell-mediated immune responses to staphylococcal antigens has been emphasized (Ficker, Am J Opthalmol., 1991, 15; 111(4):473-479).
Dry eye disease is a disorder due to an insufficient quantity of tears. The signs and symptoms of dry eye disease include ocular surface staining, eyelid swelling and redness, ocular irritation and foreign body sensation (gritty or sandy eyes). The quantity of tears can be reduced by either a failure to produce a sufficient amount of tears or by rapid evaporation of the tear film. Bron et al. (The Ocular Surface, 2: 149-164) disclose that the tear film lipid layer is the major barrier to evaporation from the ocular surface. A decrease in the thickness or functional integrity of the tear film may cause evaporative dry eye. Obstructive meibomian gland dysfunction is the most common cause of evaporative dry eye.
It has been suggested that chronic blepharitis can have an inflammatory etiology that is not associated with infection (Seal, Br J. Opthalmol., 1985, 69(8):604-611). Some studies have demonstrated that only a small proportion of patients with meibomian gland dysfunction (Mathers, Cornea., 1996, 15(2): 110-119) and blepharitis have evidence of an active infection or show the production of staphylococcal toxins (Seal, Opthalmology., 1990, 97(12): 1684-1688). Histological studies have detected inflammatory cell infiltrates containing neutrophils and lymphocytes in the corium and epidermis of blepharitis patients. A chronic nongranulomatous inflammatory reaction is observed in most cases of chronic blepharitis and blepharoconjunctivitis (Yanoff, Ocular pathology. 3rd ed. Lippincott Williams & Wilkins Publishers, 1989; 171-172). The pathophysiology of blepharitis is not well understood, but current consensus is that bacteria, altered meibum lipid composition and inflammation are the major contributors to the process.
The inflammatory aspects of blepharitis have been treated with topical steroids as well as systemic tetracycline for three months or longer. However, the well known side effects of steroid use and long term systemic antibiotic use make these treatment regimes less than optimal. Further, antibiotic ointments have been used to treat the overgrowth of normal bacterial flora in this disease. However, topical antibiotic treatment has not been used to address the inflammatory aspects of blepharitis.
Azithromycin is a macrolide antibiotic. AZASITE® (azithromycin ophthalmic solution) is a 1% sterile aqueous topical ophthalmic solution of azithromycin formulated in DURASITE® (polycarbophil, edetate disodium, sodium chloride). AZASITE® is approved by the U.S. Food and Drug Administration (FDA) for treatment of bacterial conjunctivitis, caused by susceptible isolates of CDC coryneform group G, Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis group, and Streptococcus pneumoniae (AZASITE® Package Insert, 2007). The recommended dosage regimen for the treatment of bacterial conjunctivitis is as follows: instill 1 drop in the affected eye(s) twice daily, 8 to 12 hours apart for the first 2 days and then instill 1 drop in the affected eye(s) once daily for the next 5 days (AZASITE® Package Insert, 2007).
Despite the high prevalence of the disease, blepharitis is a poorly understood clinical entity. The present therapies such as warm compresses, lid cleansing, oral nutritional supplements, and oral tetracycline antibiotics present compliance difficulties and disappointing results. Therefore, there is a need for an effective and safe method to treat the inflammatory aspects of blepharitis.